DESCRIPTION (Applicant's Abstract): The proposed research will explore interactions between the immune system and learning/memory processes by testing the hypothesis that pro-inflammatory cytokines selectively influence memory processes mediating hippocampally dependent contextual fear conditions. To determine if pro-inflammatory cytokines are involved in producing the impairment caused by peripheral LPS administration: (1) LPS will be injected while macrophages are inhibited by gadolinium chloride to determine if macrophage activation is necessary to observe the impairment in contextual fear caused by LPS; (2) LPS will be injected concurrently with either a peripheral IL-1beta receptor antagonist, TNF binding protein, or IL-6 antibody to determine if these cytokines are involved in producing the impairment in contextual fear; and (3) zymosan, another immune activator that induces the release of pro-inflammatory cytokines, will be injected to determine if it also impairs contextual but not auditory-cue fear. To determine if central IL-1beta activity is necessary to observe the impairment in contextual fear caused by LPS: (1) LPS will be injected concurrently with a central intracerebroventricular (i.c.v.) IL-1beta receptor antagonist; and (2) LPS will be injected concurrently with hippocampal microinjeted IL-1beta receptor antagonist. To determine if other variables, such as social isolation, that selectively impair contextual fear do so through inducing an increase in hippocampal IL-1beta: (1) it will be determined whether social isolation increases IL-1beta mRNA, and (2) rats will be conditioned and isolated in the presence of hippocampally administered IL-1beta receptor antagonist.